Personally I thought the Niightstalkers were great. Abigail (Jessica Biel) was just amazing. King was okay, although I do wish he'd wash his mouth out.
As for new villains, how about Blade and the Nightstalkers go on a trip to Mexico after hearing reports of a clan of vampires there. The new villain would be Mexican vampire, the Lord of Mictlampa.
Or they could go to South America and battle an army of Chupacabras.
No Blade fighting Satan or Chupacabras! lol
The only possible direction I see is to introduce Morbius.
Morbius- Michael Morbius is a Nobel Prize winning biochemist, who just happens to have a rare blood disease. In the search for a cure he turned himself into the living vampire. He originated in the Spider-Man comic books.His first introduction was in the early `70's.And continued throughout the '80's with appearances in varied Marvel comics.
Morbius?He can't be put in a Blade movie, that's why they create Nomak.
The copyright on Morbius character for a comic book movie is owned by another company.Anyway Morbius?He's basically a character that reminds to Nomak, and he doesn't seems to be a great enemy like Nomak, La Magra or Drake.
About Drake, do you all remember Blade Trinity final?Drake doesn't totally disintegrate into ashes like other vampires.
It means he can be in a suspended animation state to recover from the massive injury of the virus, and in Blade 4, Drake will come back immune to the virus, it means that anything can stop him.
He'll see that Blade is still hunting vampires, and offended by the way he lose the battle, he would search Blade for a rematch.Sabotating the NS and Blade's operations, killing people changing his form into that of Blade, and then beating the living crap out of him in demonic form, leaving him severally injured, and saying he's not ready to die.
Also it can be a great occasion to explain Drake's origins better.
Considering that now Drake is immune to to anything they can use against him, the final showdown with Blade would be the end for both of them, maybe in the temple where Drake was sleeping from thousands of years, and here Blade and the NS will find out that the only way to kill Drake is through the blood of a Daywalker.It means that Blade will stab himself with the sword and then hit Drake, but is also means that after Drake's death, the several injuries reported in the battle against Drake's Beast Form will kill our hero.